Liver Proteome of Mice with Distinct Genetic Susceptibilities to Fluorosis Treated with Different Concentrations of F in the Drinking Water Zohaib Nisar Khan 1 & Isabela Tomazini Sabino 1 & Carina Guimarães de Souza Melo 1 & Tatiana Martini 1 & Heloísa Aparecida Barbosa da Silva Pereira 1,2 & Marília Afonso Rabelo Buzalaf 1 Received: 17 October 2017 /Accepted: 10 April 2018 # Springer Science+Business Media, LLC, part of Springer Nature 2018 Abstract Appropriate doses of fluoride (F) have therapeutic action against dental caries, but higher levels can cause disturbances in soft and mineralized tissues. Interestingly, the susceptibility to the toxic effects of F is genetically determined. This study evaluated the effects of F on the liver proteome of mice susceptible (A/J) or resistant (129P3/J) to the effects of F. Weanling male A/J (n = 12) and 129P3/J (n = 12) mice were housed in pairs and assigned to two groups given low-F food and drinking water containing 15 or 50 ppm F for 6 weeks. Liver proteome profiles were examined using nano-LC-ESI-MS/MS. Difference in expression among the groups was determined using the PLGS software. Treatment with the lower F concentration provoked more pronounced alter- ations in fold change in liver proteins in comparison to the treatment with the higher F concentration. Interestingly, most of the proteins with fold change upon treatment with 15 ppm F were increased in the A/J mice compared with their 129P3/J counter- parts, suggesting an attempt of the former to fight the deleterious effects of F. However, upon treatment with 50 ppm F, most proteins with fold change were decreased in the A/J mice compared with their 129P3/J counterparts, especially proteins related to oxidative stress and protein folding, which might be related to the higher susceptibility of the A/J animals to the deleterious effects of F. Our findings add light into the mechanisms underlying genetic susceptibility to fluorosis. Keywords Liver . Fluoride . Fluorosis . Proteomics . Genetic susceptibility Introduction Fluorine is not only a common element present in the earth crust, but it is also found in the form of fluoride (F) in the soils, rocks, and water throughout the world. Higher concentrations are found in the areas where there have been recent/past py- roclastic activities or geologic uplift. In addition, fluoride is broadly employed in many industrial processes nowadays. The major sources of systemic fluoride exposure are the diet (food and water) and dental products, especially toothpastes [1]. Mild doses of fluoride have therapeutic action against den- tal caries while elevated levels, through intake of water, tooth- pastes, and diets containing high F levels will increase the body burden. The therapeutic window is very narrow, and there has been a lot of discussion concerning the appropriate levels of F intake to provide the maximum benefit (caries prevention) with minimum risk to cause disbenefits [2]. Once absorbed by the gastric intestinal system, F is distrib- uted to all soft and mineralized tissues via the bloodstream [3]. Despite the most common adverse effects of excessive F in- take are seen in the mineralized tissues (teeth and bones; den- tal and skeletal fluorosis, respectively) [4, 5], several studies that report the negative effects of F in soft tissues, such as the testis [6, 7], thyroid gland [8, 9], spleen [10, 11], liver [12], kidney [13, 14], and brain [15, 16], have been published. Interestingly, the susceptibility to the toxic effects of F appears to be genetically determined. There are reports in the literature of populations that tend to develop higher levels of dental fluorosis than it would be expected from their background exposure to F [17–19]. Moreover, it was reported that inbred mice strains have different sus- ceptibilities to dental fluorosis. The A/J strain is * Marília Afonso Rabelo Buzalaf mbuzalaf@fob.usp.br 1 Department of Biological Sciences, Bauru School of Dentistry, University of São Paulo, Al. Octávio Pinheiro Brisolla, 9-75, Bauru, São Paulo 17012-901, Brazil 2 Department of Genetics and Evolution, Center of Biological Sciences and the Health, Federal University of São Carlos, Washington Luis, Km 235, São Carlos, São Paulo 13560-970, Brazil Biological Trace Element Research https://doi.org/10.1007/s12011-018-1344-8